Biophysicists Grow Pretty Bacteria In Petri Dishes To Find Antibiotics

Biophysicists are growing Petri dishes of different species of bacteria in order to develop new antibiotics. The bacteria are subjected to different temperatures and have limited food sources inside the dish. Despite these conditions, most colonies tend to communicate and reproduce. Their growth results in unique patterns of varying colors--a sort of "bacteria painting." Researchers are hoping to learn more about the strategies the bacteria use to thrive, in order to find weaknesses that new drugs could exploit.

There was a time when doctors thought antibiotics could cure all. It's a different story today as drug-resistant bacteria emerge in places like hospitals and schools. To keep up with changes in bacterial behavior, scientists are fighting bacteria using an artistic approach.

Biophysicist Herbert Levine's Petri dishes look like an exhibit at a modern art museum. His beautiful images are actually made from bacteria similar to the ones that cause deadly diseases. Dr. Levine uses bacteria in Petri dishes in his quest to discover the next super drug. He's fighting a new generation of bacterial infections that includes MRSA, a flesh-eating disease resistant to antibiotics.

"We thought we had a whole arsenal of antibiotics and these would always work ý but the bacteria are smarter than we used to give them credit for being," said Dr. Levine, who works at the University of California in San Diego.

Dr. Levine and his team have gone back to the basics of biology. They have created bacteria patterns by changing the temperature and limiting the food sources inside Petri dishes. Despite harsh conditions, the colonies find ways to communicate and reproduce.

"If we can understand what strategies they're using, we can devise methods to defeat those strategies," Dr. Levine said.

Through Dr. Levine's work, scientists have learned bacteria are very resourceful. They enclose themselves in areas antibiotics can't find. They also soak up antibiotics to keep the rest of their colony safe and transform themselves into new strains that are less sensitive to the drugs.

"If that basic understanding of nature leads to better life for humanity, then, of course, that makes us even more excited," Dr. Levine said.

Along the way, scientists turned the study of bacteria into an art form.

Dr. Levine and his colleague, Eshel Ben-Jacob, use the patterns to create computer models. One day those models could be the basis for new medicines that fight all types of bacteria.

WHAT IS MRSA: MRSA is a common cause of skin infections; it can also cause pneumonia, ear infections and sinusitis. MRSA bacteria are sometimes dubbed 'superbugs' because they are highly resistant to common antibiotics like penicillin, making infections difficult to treat effectively. Bacteria are highly adaptive, and over time they naturally develop resistance, protecting them from incoming germs (and antibiotics) and making them harder to kill. If MRSA enters the body through the skin, it can cause irritating skin infections, but if it enters the lungs or bloodstream, it can cause serious blood infections, pneumonia, even death. MRSA infection rates in the US have been increasing since 1970, largely because surveillance programs to monitor its spread are not effective. Other countries, such as the Netherlands, Sweden and Denmark have all but eliminated MRSA from their hospitals through such surveillance programs, which focus on screening patients for MRSA at admission and isolating any carriers.

DRUG RESISTANCE: Bacteria are highly adaptive, and over time they naturally develop resistance, protecting them from incoming germs (and antibiotics), which makes them more difficult to kill. If someone has strep throat, for example, repeated exposure to penicillin and amoxicillin can result in a throat full of bacteria that can shield strep germs from the older drugs. The surviving bacteria then reproduce more and become more dominant. Sometimes parents discontinue antibiotic medication prematurely when they or their children begin to feel better, so the strep germ isn't entirely killed off, leading to much more severe infections requiring the use of even stronger drugs later on. This can also happen with many other infections inside the body and on the skin.

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Blocking an Oncogene in Liver Cancer Could Be Potential Therapy Option

Scientists have found that a synthetic molecule they designed can block activation of a gene in liver cancer cells, halting a process that allows some of those cancer cells to survive chemotherapy.

Without the interference of this gene's function, certain liver cancer cells appear to be protected from the toxic effects of chemotherapy drugs.

Blocking the oncogene, called STAT3, prevents a protein from protecting the cells, the research suggests. As a result, more liver cancer cells succumb to treatment.

Researchers hope an anti-cancer drug based on the molecule's design eventually will be developed for use in patients, after the required animal and clinical testing is completed.

The scientists have seen similar results in studies using this experimental molecule, called LLL12, to block STAT3 as a way to induce cell death in breast and pancreatic cancer cells.

"For patients, it would be easy to use an intravenous drug based on this small molecule, which is relatively cheap and easy to manufacture," said Jiayuh Lin, senior author of the study and an associate professor of pediatrics at Ohio State University.

"We also have seen signs that blocking STAT3 could block other downstream targets, and could affect other STAT3-regulated genes that can turn normal cells into cancer cells. We believe this molecule has a lot of potential for cancer therapy."

Lin led the team of scientists who designed LLL12 using powerful computers and a computational method called structure-based design. The group reported on its creation earlier this year.

This new study is published in a recent issue of the Journal of Biological Chemistry.

The protein in this process is called interleukin-6, or IL-6. It is a cytokine, a chemical messenger that causes inflammation, and can have both beneficial and damaging effects in the body. Previous research by other scientists has shown that high levels of IL-6 in the blood are associated with hepatocellular carcinoma, the most common type of liver cancer.

The fifth most common cancer in humans, liver cancer remains one of the most difficult to successfully treat. Patients' overall five-year survival rate is about 10 percent, according to the American Cancer Society.

In this study, the researchers observed that liver cancer cells known to be resistant to a common chemotherapy drug, doxorubicin, had higher levels of IL-6 than did other liver cancer cells -- an indication that the protein likely fosters the drug resistance. Subsequent tests showed that these resistant cells with high IL-6 also had higher levels of STAT3 phosphorylation than did other cells.

To further demonstrate this relationship between the protein and cell survival, Lin and colleagues pretreated liver cancer cells with the chemotherapy drug and then followed with different doses of IL-6. The addition of IL-6 rescued these cells from chemo-induced death.

Alternately, when the scientists introduced an antibody to inhibit IL-6 in drug-resistant cancer cells and then followed with doses of doxorubicin, 70 percent more of the cells treated with the IL-6 inhibitor died compared to cells treated with the chemo drug alone -- a sign that the loss of IL-6 lowers survival in these particular cancer cells.

After determining in cell cultures that IL-6 activates STAT3 to help perform this cell survival function, the researchers focused on testing the effects of blocking the gene alone.

They first used silencing RNA, or siRNA, to prevent activation of the STAT3. More of the siRNA-treated cells died than did cells in which the STAT3 was not blocked.

"At this point, we know that STAT3 plays an important role, and that IL-6 depends on STAT3 to protect cells from dying," said Lin, also an investigator in Ohio State's Comprehensive Cancer Center and the Center for Childhood Cancer at Nationwide Children's Hospital.

The scientists then turned to the synthetic molecule, LLL12, which was designed specifically to tuck itself into a gap in STAT3's two-part structure and disable its activation.

The researchers introduced LLL12 to four types of liver cancer cells and followed with a dose of IL-6. The IL-6 protein had no protective effect on cells treated with the molecule, meaning it could not turn on STAT3, a required step in protecting the cells from death.

To be sure, they also tested how cells with and without LLL12 treatment responded to chemotherapy. The small molecule treatment completely blocked resistance to the drug, Lin said, even in the types of liver cancer cells that express the highest IL-6 levels and are most resistant to doxorubicin.

Importantly, the researchers were able to determine that inhibiting STAT3 activation did not affect other proteins that are induced by IL-6 for potentially beneficial reasons. The small molecule also did not exacerbate the effects of chemotherapy on normal liver cells.

Lin and colleagues are currently testing the effects of LLL12 in multiple myeloma, breast and colon cancer cells, in which the IL-6/STAT3 pathway also plays an important role.

This work was supported by the grants from the National Institutes of Health, the Pancreatic Cancer Action Network -- American Association of Cancer Research, and the National Foundation for Cancer Research.

Co-authors of the study include Yan Liu of the Department of Pediatrics, and Pui-Kai Li and Chenglong Li of the Division of Medicinal Chemistry and Pharmacognosy, all at Ohio State.

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Ancient Viral Invasion Shaped Human Genome

Scientists at the Genome Institute of Singapore (GIS), a biomedical research institute of the Agency for Science, Technology and Research and their colleagues from the National University of Singapore, Nanyang Technological University, Duke-NUS Graduate Medical School and Princeton University have recently discovered that viruses that 'invaded' the human genome millions of years ago have changed the way genes get turned on and off in human embryonic stem (ES) cells.

The study provides definitive proof of a theory that was first proposed in the 1950s by Nobel Laureate in physiology and medicine, Barbara McClintock, who hypothesized that transposable elements, mobile pieces of the genetic material (DNA), such as viral sequences, could be "control elements" that affect gene regulation once inserted in the genome.

This finding is an important contribution to the advancement of stem cell research and to its potential for regenerative medicine. Led by GIS Senior Group Leader Dr Guillaume Bourque, the study was published in Nature Genetics on June 6, 2010.

Through the use of new sequencing technologies, the scientists studied the genomic locations of three regulatory proteins (OCT4, NANOG and CTCF) in human and mouse embryonic stem (ES) cells. Interestingly, while the scientists found a lot of similarities, they also found many differences in the methods and the types of genes that are being regulated in humans. In particular, it was discovered that specific types of viruses that inserted themselves in the human genomes millions of years ago have dramatically changed the gene regulatory network in human stem cells.

"This study is a computational and experimental tour de force. It provides undeniable evidence that some transposable elements, which are too often dismissed as merely junk DNA, are key components of a regulatory code underlying human development," said Dr Cedric Feschotte, Associate Professor of the University of Texas Arlington.

Scientists at the Genome Institute of Singapore (GIS), a biomedical research institute of the Agency for Science, Technology and Research and their colleagues from the National University of Singapore, Nanyang Technological University, Duke-NUS Graduate Medical School and Princeton University have recently discovered that viruses that 'invaded' the human genome millions of years ago have changed the way genes get turned on and off in human embryonic stem (ES) cells.

The study provides definitive proof of a theory that was first proposed in the 1950s by Nobel Laureate in physiology and medicine, Barbara McClintock, who hypothesized that transposable elements, mobile pieces of the genetic material (DNA), such as viral sequences, could be "control elements" that affect gene regulation once inserted in the genome.

This finding is an important contribution to the advancement of stem cell research and to its potential for regenerative medicine. Led by GIS Senior Group Leader Dr Guillaume Bourque, the study was published in Nature Genetics on June 6, 2010.

Through the use of new sequencing technologies, the scientists studied the genomic locations of three regulatory proteins (OCT4, NANOG and CTCF) in human and mouse embryonic stem (ES) cells. Interestingly, while the scientists found a lot of similarities, they also found many differences in the methods and the types of genes that are being regulated in humans. In particular, it was discovered that specific types of viruses that inserted themselves in the human genomes millions of years ago have dramatically changed the gene regulatory network in human stem cells.

"This study is a computational and experimental tour de force. It provides undeniable evidence that some transposable elements, which are too often dismissed as merely junk DNA, are key components of a regulatory code underlying human development," said Dr Cedric Feschotte, Associate Professor of the University of Texas Arlington.

The comparisons between the human and mouse model system in the study of gene regulatory networks help to advance the understanding of how stem cells differentiate into various cell types of the body. "This understanding is crucial in the improved development of regenerative medicine for diseases such as Parkinson's disease and leukaemia," said Dr Bourque. "Despite the advantages of using mouse ES cells in the study of gene regulatory networks, further research must focus more directly on human stem cells. This is due to the inherent challenges of converting the results of studies done from one species to that of the next. More research will need to be done in both human and non-human primate stem cells for findings on stem cells to be used in clinical application."

Prof Raymond L. White, PhD, Rudi Schmid Distinguished Professor of Neurology, University of California said, "The paper reports very exciting new findings that establish a new and fundamentally distinct mechanism for the regulation of gene expression. By comparing the genomes of mouse with human, the scientists were able to show that the binding sites for gene regulatory factors are very often not in the same place between the two species. This by itself would be very surprising, but the investigators go further and demonstrate that many of the sites are imbedded within a class of DNA sequences called "transposable" elements because of their ability to move to new places in the genome. There are a number of such elements believed to be the evolutionary remnants of viral genomes, but it was very surprising to learn that they were carrying binding sites for regulatory elements to new locations. These changes in regulation would be expected to create major changes in the organisms which carry them. Indeed, many think that regulatory changes are at the heart of speciation and may have played a large role in the evolution of humans from their predecessors. This is likely to be a landmark paper in the field."

Dr Eddy Rubin, Director of the U.S. Department of Energy Joint Genome Institute and Director of the Genomics Division at Lawrence Berkeley National Laboratory in Berkeley added, "This study using a comparative genomics strategy discovered important human specific properties of the regulatory network in human ES cells. This information is significant and should contribute to helping move the regenerative medicine field forward."

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Hope for a New Treatment for Bone Cancer: Can 'Friendly' Bacteria Kill Cancer Cells?

The Bone Cancer Research Trust has launched Bone Cancer Awareness Week and has funded a new project at the University which is testing a theory that 'friendly bacteria' can be used to kill bone cancer cells.

Researchers at the School of Clinical Sciences' Division of Pre-Clinical Oncology are investigating whether modifying a harmless type of the bacterium, Salmonella typhimurium, can produce molecules which kill cancer cells in osteosarcoma, a primary bone cancer. The scientists are using a clinically safe form of the bacterium which has been found to localise to tumour tissue rather than healthy tissue.

Osteosarcoma (OS) is the most common type of primary bone cancer and although rare, can be particularly distressing because it affects mostly children and adolescents. Cases tend to have a poor outlook because the cancer often does not respond well to the treatments currently available. There have been few new treatments for OS in the past 20 years and more research and techniques to fight it are urgently needed as more than 2,000 children and young people are diagnosed with the disease every year in the UK.

A main challenge in developing better treatments for bone cancer is finding a much more effective way of targeting anti-cancer drugs at the tumour. Many drugs are given by intravenous injection and use the body's venous system to reach their target, but tumours in bone tend to have a low blood supply.

Dr Coughlan's aim is to modify the Salmonella bacteria to act as a vehicle for cancer-killing agents. It's believed special molecules, called RNA interference molecules, when produced in the bacteria will be more effectively released into malignant cells destroying the levels of cancer-causing molecules there.

It's hoped this research will eventually lead to a treatment for bone cancer that is better targeted at tumours and doesn't affect normal, healthy tissue.

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